Hepatitis C is a major health problem world-wide. The World Health Organization estimates that 170 million people are chronic carriers of the hepatitis C virus (HCV), with 4 million carriers in the United States alone. In the United States, HCV infection accounts for 40% of chronic liver disease and HCV disease is the most common cause for liver transplantation. HCV infection leads to a chronic infection and about 70% of persons infected will develop chronic histological changes in the liver (chronic hepatitis) with a 10-40% risk of cirrhosis and an estimated 4% lifetime risk of hepatocellular carcinoma. The CDC estimates that each year in the United States there are 35,000 new cases of HCV infection and approximately ten thousand deaths attributed to HCV disease.
Setrobuvir, a 5,6-dihydro-1H-pyridin-2-one compound, specifically N-(3-{(1R,2S,7R,8S)-3-[(4-fluorophenyl)methyl]-6-hydroxy-4-oxo-3-azatricyclo[6.2.1.02,7]undec-5-en-5-yl}-1,1-dioxo-1,4-dihydro-1λ6,2,4-benzothiadiazin-7-yl)methanesulfonamide (U.S. Pat. No. 7,939,524, herein expressly incorporated by reference) is one of the compounds useful in treating HCV. U.S. Pat. No. 7,939,524 and WO 2010/42834 both disclose Setrobuvir as well as method(s) of making same.
A key intermediate in the preparation of Setrobuvir is N-(4-methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid methyl ester. A number of methods of making this intermediate in the preparation of Setrobuvir have been noted in U.S. Pat. No. 7,939,524, and WO 2010/42834, but these routes have some drawbacks. Fox example, in WO2010/42834, the production of the electron-rich diaminobenzene intermediate 2,5-diamino-benzenesulfonamide is prone to color-generation issues that need to be reduced in the next intermediate, or it can result in color issues in the final product (Setrobuvir). Additionally, the WO2010/42834 route can also result in a chloro impurity (identified via LC/MS in the key intermediate N-(4-methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid methyl ester.
Accordingly, a novel method for preparing Setrobuvir via the key intermediate N-(4-methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid methyl ester is required to avoid the production of the electron rich diaminobenzene intermediate, and possible color issues in Setrobuvir, as well as to eliminate the chloro impurity in the key intermediate N-(4-methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid methyl ester.